Breast cancer genomics involves the study of genetic and genomic alterations in breast cancer to understand tumor biology, classify subtypes, guide treatment, and predict outcomes.
Genetic risk factors include common, single nucleotide variants with low penetrance, as well as rare but highly penetrant variants in BRCA 1, BURCA2, and other genes identified as pathogenic for breast cancer.
Pathogenic variants have differential impacts on breast cancer risk, depending on the affected gene and specific mutation.
Breast cancer, family, history, and non-genetic risk factors for disease likely introduce additional risk variability.
Genomic changes in breast cancer include both inherited gremlin mutations and acquired somatic mutations that drive tumor progression.
Breast cancers can be classified into major subgroups based on structural DNA changes, such as gene amplifications, extrachromosomal DNA and genome instability.
In a study of almost 68,000 women with a pathogenic variant and a first-degree family history of breast cancer had an estimated 22.5 risk of breast cancer by age 50 years and a 51.2% risk between age 50 and 80 years compared within 9.4% risk by age 50 years and a 29.7% risk between ages 50 and 80 years in women with a pathological variant but no family history.
The main genomic subtypes include: Luminal A and B (hormone receptor-positive) HER2-enriched (HER2-positive) Triple-negative/basal-like (lacking hormone receptors and HER2)
High-risk hormone-receptor positive and HER2-positive tumors often show localized gene amplifications and extrachromosomal DNA carrying oncogenes.
Triple-negative breast cancers typically demonstrate widespread genomic instability and DNA repair deficiencies.
Lower-risk, hormone-receptor positive/HER2-negative tumors usually have relatively stable genomes.
Frequently mutated genes in breast cancer include PIK3CA, TP53, ERBB2 (HER2), FGFR1, and CCND1.
Germline mutations in BRCA1, BRCA2, and other genes like PALB2, TP53, CHEK2, and ATM substantially increase breast cancer risk.
These genes are often involved in DNA repair, cell growth regulation, and hormone signaling.
Genomic profiling allows for the selection of targeted therapies, especially in advanced/metastatic disease.
For instance, tumors with HER2 amplification respond to anti-HER2 drugs, while those with DNA repair defects with BRCA1/2 mutation may benefit from PARP inhibitors.
Gene expression assays (Oncotype DX, MammaPrint) analyze patterns of gene activity to assess recurrence risk and the likely benefit of chemotherapy in early-stage disease.
Clinical trials increasingly use genomics to tailor treatments to actionable mutations.
About 5–10% of breast cancers are due to inherited (germline) mutations, while most are caused by somatic changes acquired during a person’s lifetime.
Early mutational events shape a tumor’s behavior and prognosis from the outset.
Genomic advances continue to fuel personalized medicine in breast cancer, offering increasingly precise prognostic and predictive tools.
Breast cancers at all stages are defined by the structure of their genomes, suggesting that genomic architecture plays a fundamental role in its behavior and progression.
BRCA1/BRCA2 mutations remain among the most clinically significant findings.
People with inherited BRCA1 mutations tend to develop a subtype of breast cancer known as triple negative breast cancer demonstrating how germline genetics influence tumor biology.
PIK3CA mutations have associated approval of inavolisib (Itovebi) plus palbociclib and fulvestrant for hormone receptor–positive, HER2-negative, PIK3CA-mutated advanced breast cancer .
Genomic testing has become standard practice for treatment decisions:
Prognostic gene expression assays like MammaPrint and Oncotype DX help determine chemotherapy benefit in early-stage disease, with utility of MammaPrint and BluePrint for informing axillary surgery decisions in the neoadjuvant setting.
Predictive biomarkers guide targeted therapy selection, including HER2 testing for trastuzumab, hormone receptor status for endocrine therapy, and BRCA testing for PARP inhibitors.
Genomic and transcriptomic analysis has identified novel signatures associated with response to neoadjuvant chemotherapy and help predicting which patients will benefit from pre-surgical treatment.
The Oncotype DX test is a 21 gene assay using reverse transcription polymerous chain reaction, shown to be both prognostic and predictive of chemotherapy benefit, in patients with node negative and not positive breast cancer.
The test generates a recurrent score from 0 to 100 estimating the risk of distant recurrence and the likely benefit of chemotherapy.
The study finds that endocrine therapy alone is non-inferior to chemotherapy, followed by endocrine therapy for invasive disease free survival in patients with a recurrent score of 11 to 25.
The mammaprint (MP) is a 70 Gene micro array based essay that categorizes tumors into high, or low risk of distant recurrence based on the expression of 70 genes.
The prediction analysis of microarray 50 (parentheses (PAM 50) Gene signature away measures the expression of 50 genes in breast cancer, categorizes tumors into four molecular the subtypes: luminal A, luminal B, ERBB2 enriched, and basil like.
It has a score of correlates with the probability of distant recurrence at 10 years.